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A new cell-permeable peptide allows successful allogeneic islet transplantation in mice

Nature Medicine volume 10, pages 305–309 (2004)Cite this article

Abstract

Calcineurin inhibitors such as cyclosporine A and FK506 have been used for transplant therapy and treatment of autoimmune diseases. However, the inhibition of calcineurin outside the immune system has a number of side effects, including hyperglycemia. In the search for safer drugs, we developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system1,2. This peptide provided immunosuppression for fully mismatched islet allografts in mice. In addition, it did not affect insulin secretion, whereas FK506 caused a dose-dependent decrease in insulin secretion. Cell-permeable peptides can thus provide a new strategy for drug development and may eventually be useful clinically.

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Figure 1: Transduction of 11R-peptides into Jurkat cells and inhibition of NFAT.
Figure 2: Effect of 11R-peptides on T-cell response.
Figure 3: Effect of 11R-peptides on islet transplantation.
Figure 4: Effects of FK505 and 11R-VIVIT on insulin secretion.

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Notes

  1. NOTE: In the version of this article originally published online, the peptide sequences in the first sentence of the Methods section, "Peptide synthesis," was printed incorrectly. The correct sequences are 11R-VIVIT, RRRRRRRRRRR-GGG-MAGPVIVITGPHEE; and 11R-VEET, RRRRRRRRRRR-GGG-MAGPPHIVEETGPHVI. The mistake has been corrected for the HTML and print versions of the article.

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Acknowledgements

We thank A. Rao and P. Hogan (Harvard University) for providing the GFP-NFAT-1 plasmid and other reagents; S. Bonner-Weir (Harvard University) and T. Takahashi (Tokyo University) for discussion and comments on this manuscript; and T. Ogawa and T. Shirai for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (medical genome science) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the Life Science Project of 21st Century, Japan, and by the Regional Research & Development Consortium Project.

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Authors and Affiliations

  1. Department of Physiology and Transplant and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Hirofumi Noguchi, Masayuki Matsushita, Akiyoshi Moriwaki, Kazuhito Tomizawa, Sheng-Tian Li & Hideki Matsui

  2. Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Hirofumi Noguchi, Teru Okitsu, Naoya Kobayashi & Noriaki Tanaka

  3. Department of Transplantation and Immunology, Kyoto University Hospital, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Hirofumi Noguchi, Teru Okitsu, Shinichi Matsumoto & Koich Tanaka

  4. Department of Pathology, Harvard Medical School and the Center for Blood Research, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Sunghyun Kang

  5. Protein Therapy, Preventure Program, Office of Technology Transfer, Japan Science and Technology Corporation, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Hideki Matsui

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  1. Hirofumi Noguchi
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Correspondence to Masayuki Matsushita.

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Noguchi, H., Matsushita, M., Okitsu, T. et al. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nat Med 10, 305–309 (2004). https://doi.org/10.1038/nm994

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